Changes in aberrant DNA methylation after Helicobacter pylori eradication: A long-term follow-up study Cheol Min Shin 1 , Nayoung Kim 1,2 , Hye Seung Lee 3 , Ji Hyun Park 2 , Soyeon Ahn 4 , Gyeong Hoon Kang 5 , Jung Mogg Kim 6 , Joo Sung Kim 2 , Dong Ho Lee 1,2 and Hyun Chae Jung 2 1 Department of Internal Medicine, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea 2 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea 3 Department of Pathology, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea 4 Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seoungnam, Gyeonggi-do, Korea 5 Department of Pathology, Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea 6 Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea Changes of DNA methylation in gastric mucosae after eradication of Helicobacter pylori have not been clarified yet. From this background, we investigated time course of DNA methylation following H. pylori eradication in 221 successfully H. pylori eradicated subjects with endoscopic follow-up at least for 6 months, including 114 controls, 53 subjects with gastric dyspla- sia and 54 patients with early gastric cancer. All dysplasia and gastric cancer patients underwent endoscopic resection at the time of enrollment. The methylation levels in LOX, APC and MOS genes from noncancerous gastric mucosae using quantitative methylation-specific PCR, as well as the histologic findings of gastric mucosae, were compared before and after eradication. Average follow-up duration was 26.0 months (range: 6 to 76 months). H. pylori eradication decreased methylation levels in LOX (p-value for slope < 0.001) but not in APC. In MOS, decrease of its methylation level following H. pylori eradication was significant among controls without intestinal metaplasia (IM) (p-value for slope < 0.05); however, it was not observed among patients with IM or those with dysplasia or gastric cancer. After H. pylori eradication, methylation level in MOS persistently increased in patients with dysplasia or gastric cancer (p < 0.01). In conclusion, H. pylori eradication decreases aberrant DNA methylation with gene-specific manner. Methylation level in MOS is associated with IM and may be used as a surrogate marker for gastric cancer risk, regardless of H. pylori eradication history. In Korea, the prevalence of Helicobacter pylori (H. pylori) infection and the incidence of gastric cancer are unacceptably high. A recent survey showed a decreasing trend in the sero- prevalence of H. pylori from 66.9% in 1998 to 59.6% in 2005, 1 but gastric cancer remains one of the most common cancers in Korea; a recent survey reported an age-standar- dized incidence rate of 64.2 in males and 25.4 in females per 100,000. 2 Epidemiological studies have suggested that H. pylori infection is an important risk factor for gastric cancer. Gas- tric carcinogenesis is regarded as a multistep process with an intestinal metaplasia (IM)-dysplasia-invasive carcinoma sequence, which is known to be initiated by H. pylori infec- tion that causes a chronic active inflammation with severe oxidative damage of the gastric mucosa. 3,4 In this context, it could be speculated that eradication of H. pylori might termi- nate this sequence and eventually reduce the risk for gastric cancer. In addition, premalignant lesions such as atrophic gastritis or IM might be improved by its eradication. Preclini- cal studies have demonstrated that H. pylori eradication pre- vented gastric cancer and reversed mucosal atrophy and IM in mouse or Mongolian gerbil models. 5–7 In the clinical set- ting, however, the issue whether the anti-Helicobacter therapy can reduce the risk for gastric cancer continues to be debated, 8,9 and previous studies on the effects of H. pylori eradication on the improvement of atrophy or IM have been only inconsistent. 10–13 Promoter CpG island hypermethylation and global DNA hypomethylation are frequently found during gastric carcino- genesis and H. pylori infection has been reported to be asso- ciated with aberrant DNA methylation. 14–19 Several lines of studies have been consistently reported that H. pylori-associ- ated active inflammation was responsible for the promoter Key words: gastric cancer, Helicobacter pylori, inflammation, methylation Additional Supporting Information may be found in the online version of this article. Grant sponsor: Global Core Research Center (GCRC), National Research Foundation (NRF), Ministry of Education, Science and Technology (MEST), Republic of Korea; Grant number: 2012- 0001185 DOI: 10.1002/ijc.28219 History: Received 25 Oct 2012; Accepted 3 Apr 2013; Online 18 Apr 2013 Correspondence to: Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 300 Gumi- dong, Bundang-gu, Seongnam, Gyeonggi-do 463-707, South Korea, Tel.: 182-31-787-7008, Fax: 182-31-787-4051, E-mail: nayoungkim49@empal.com Carcinogenesis Int. J. Cancer: 133, 2034–2042 (2013) V C 2013 UICC International Journal of Cancer IJC